US20240115578A1 - Drug composition for treating pediatric cancers - Google Patents

Drug composition for treating pediatric cancers Download PDF

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US20240115578A1
US20240115578A1 US18/271,529 US202218271529A US2024115578A1 US 20240115578 A1 US20240115578 A1 US 20240115578A1 US 202218271529 A US202218271529 A US 202218271529A US 2024115578 A1 US2024115578 A1 US 2024115578A1
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months
alectinib
alk
less
salt
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Jotaro SATO
Chie EMOTO
Mikiko NAKAMURA
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Chugai Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a pharmaceutical composition for the treatment of cancer in children under the age of 2, which comprises alectinib or a salt thereof, a liquid, a suspension, a use, a method, and the like.
  • ALK Advanced Lymphoma Kinase
  • ALK fusion genes The expression of ALK fusion genes was reported relatively early in anaplastic large cell lymphoma (hereinafter, ALCL) and inflammatory myofibroblastic tumor (hereinafter, IMT), which predominantly occur in the pediatric/adolescent and young adult generations.
  • ALCL anaplastic large cell lymphoma
  • IMT inflammatory myofibroblastic tumor
  • IMT is a relatively rare soft tissue sarcoma occurring predominantly in the lungs and soft tissues, and occurs predominantly in the teens to twenties.
  • TPM3/4-ALK fusion gene in IMT was identified, the TPM3/4-ALK fusion gene was then found in approximately 50% of IMTs and ALK translocations were reported to be frequent in pediatric cases (Non Patent Literature 3: Am J Pathol. 2000 August; 157(2): 377-84).
  • Recent studies have proven the existence of IMT cases with different combinations of ALK fusions other than the TPK3/4-ALK fusion gene, and have reported that ALK fusion genes are detected in the vast majority of IMTs (Non Patent Literature 4: Cancer Discov. 2014 August; 4(8): 889-95).
  • Non Patent Literature 5 Biochem J. 2008 Dec. 1; 416(2): 153-9
  • germline mutations of the ALK gene were found to be detected in familial neuroblastoma, which accounts for 1 to 2% of neuroblastomas
  • Non Patent Literature 6 Nature. 2008 Oct. 16; 455(7215): 930-5
  • the amplification of the ALK protein and the presence of an ATIC-ALK fusion gene have also been reported, and although there is variation among the reports, the percentage of “ALK abnormalities” was 18 to 59%
  • Non Patent Literature 7 Int J Cancer. 2002 Jul.
  • Non Patent Literature 8 Mod Pathol. 2013 June; 26(6): 772-81;
  • Non Patent Literature 9 J Clin Oncol. 2012 Jan. 20; 30(3): 308-15).
  • the percentage of “ALK abnormalities” has been reported to be high in alveolar rhabdomyosarcoma, a histological type with poor prognosis, and metastatic and recurrent cases have also been reported to have a high percentage of “ALK abnormalities” of around 70% (Non Patent Literatures 8 and 9).
  • Non Patent Literature 10 Int J Cancer. 2013 Jul.
  • Non Patent Literature 7, and Non Patent Literature 11 Mod Pathol. 2002 September; 15(9): 931-8).
  • the prognosis for recurrent cases of pediatric malignant solid tumor is poor, with a median overall survival generally ranging from 1 to 2 years regardless of the type of cancer, but there are rare cases of long-time surviving patients for single recurrences or if they are responsive to chemotherapy. Due to the rarity of recurrent pediatric malignant solid tumors, there are very few established standard treatments regardless of the type of cancer, and there is a need for an effective therapeutic drug for childhood cancer regardless of the type of cancer.
  • Crizotinib which is a first-generation ALK inhibitor, was clinically developed by the Children's Oncology Group (COG), a U.S. childhood cancer research group, for recurrent/refractory pediatric malignant solid tumors, ALK fusion gene-positive ALCL and neuroblastoma, and other malignant solid tumors including ALK fusion gene-positive IMT, and the efficacy of adult dose-equivalent crizotinib has been reported for pediatric neuroblastoma, IMT and ALCL with ALK gene abnormalities (Non Patent Literature 12: Journal of clinical oncology 2017 Oct. 1; 35(28): 3215-21).
  • ALK abnormalities are widely found in a variety of pediatric malignant solid tumors, and ALK inhibitors against ALK abnormalities are considered an important target in the development of treatment in the field of pediatric oncology.
  • a novel therapeutic drug comprising alectinib, a second-generation ALK inhibitor, as an active ingredient, for the treatment of cancer in children under the age of 2.
  • PK pharmacokinetic
  • the present invention provides a pharmaceutical composition, a liquid, a suspension, a use, and a method with the following aspects.
  • the pharmaceutical composition, liquid, suspension, use, and method of the present invention provide a pharmaceutical composition with a novel dosage and administration, which can be expected to be effective and safe in the treatment of cancer in children under the age of 2.
  • FIG. 1 is a graph showing changes in trough concentration when administering 20 mg to 80 mg of alectinib twice daily to a hypothetical Japanese patient aged less than 24 months.
  • FIG. 2 is a graph showing changes in Cmax and AUC ss for the administration of 20 mg of alectinib once daily to a hypothetical Japanese patient aged less than 13 months.
  • FIG. 3 is a graph showing changes in trough concentration when administering 20 mg to 40 mg of alectinib twice daily to a hypothetical Japanese patient aged 13 months to less than 24 months.
  • the “salt” of alectinib is preferably a pharmaceutically acceptable salt
  • examples of the “pharmaceutically acceptable salt” include hydrochlorides, hydrobromides, hydroiodides, phosphates, phosphonates, sulfates, sulfonates such as methanesulfonate and p-toluenesulfonate, carboxylates such as acetate, citrate, malate, tartrate, succinate, and salicylate, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; and ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, and tetraalkylammonium salts.
  • Hydrochlorides are preferred, with monohydrochloride being most preferred.
  • Alectinib or a salt thereof can be produced by a method known in the art (for example, the methods described in Japanese Patent No. 4588121 and WO2020/050241).
  • the monohydrochloride of alectinib may be amorphous (WO2016/021707) or crystalline. If crystalline, a crystal having peaks at the diffraction angles (20) near 8.4°, 14.0°, 16.7°, 18.8° and 23.3° in the powder X-ray diffraction pattern is preferred (WO2015/163447).
  • the amorphous form of the monohydrochloride of alectinib can be produced according to the method described in WO2016/021707, and the crystal with these peaks can be produced according to the method described in WO2015/163447.
  • Alectinib or the salt thereof is contained in an amount of 20 to 70% by weight, preferably 35 to 60% by weight, and still more preferably 45 to 50% by weight, in terms of free form, based on the total amount of the composition.
  • composition of the present invention can be formulated using additives such as excipients, lubricants, coating agents, binders, disintegrants, stabilizers, taste and odor improvers, and diluents, and using a well-known method or the methods described in, for example, Japanese Patent No. 4588121, Japanese Patent No. 4918630, Japanese Patent No. 5006987, Japanese Patent No. 5859712, and WO2020/004630.
  • Alectinib hydrochloride is a Japanese second-generation ALK inhibitor with high selective inhibitory activity against ALK, developed by Chugai Pharmaceutical Co., Ltd.
  • Alectinib hydrochloride showed high efficacy in a phase I/II trial (AF-001JP trial) in Japan on patients with ALK fusion gene-positive advanced/recurrent non-small cell lung cancer (hereinafter, NSCLC), and was approved for manufacture and marketing in Japan in July 2014 for “ALK fusion gene-positive unresectable advanced or recurrent non-small cell lung cancer” and in February 2020 for “recurrent or refractory ALK fusion gene-positive anaplastic large cell lymphoma”.
  • ALK-positive metastatic (advanced) non-small cell lung cancer resistant or intolerant to crizotinib in numerous countries
  • AK-positive advanced non-small cell lung cancer (first-line treatment) in Europe, the United States, and and the like.
  • the term “pharmaceutical composition” means a mixture containing at least one active ingredient and at least one inactive ingredient, used for the treatment or prevention of a disease.
  • active ingredient means an ingredient that exhibits the effect of interest on a living organism, and the term “inactive ingredient” means an ingredient other than an active ingredient, such as an additive.
  • the pharmaceutical composition is used in the production of a pharmaceutical preparation.
  • pharmaceutical preparation means a preparation for the treatment or prevention of a disease.
  • compositions include solid preparations and liquid preparations, but a liquid or suspension is preferred in the present invention.
  • Specific examples of solid preparations include tablets, capsules, liquids, powders, lozenges, chewables, granules, gels, and films, among which granules are preferred.
  • the pharmaceutical preparation containing the pharmaceutical composition of the present invention is produced by a well-known method using additives such as excipients, lubricants, coating agents, binders, disintegrants, stabilizers, taste and odor improvers, diluents, colorants, fluidizers, preservatives, and antioxidants.
  • additives such as excipients, lubricants, coating agents, binders, disintegrants, stabilizers, taste and odor improvers, diluents, colorants, fluidizers, preservatives, and antioxidants.
  • excipients include starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch; sugars or sugar alcohols such as lactose hydrate, fructose, glucose, mannitol, and sorbitol; anhydrous dibasic calcium phosphate, crystalline cellulose, precipitated calcium carbonate, and calcium silicate.
  • excipients include starches such as corn starch, potato starch, and corn starch, lactose hydrate, crystalline cellulose, and anhydrous dibasic calcium phosphate.
  • coating agents examples include ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, and paraffin.
  • the “disintegrant” is a component for promoting the rapid disintegration of a solid preparation after its ingestion.
  • disintegrants examples include sodium starch glycolate, low-substituted hydroxypropyl cellulose, calcium carmellose, pregelatinized starch, sodium chloride, corn starch, sodium croscarmellose, crystalline cellulose, anhydrous silicic acid, and carmellose.
  • the amount of disintegrant used is, for example, 5% or more by weight, preferably 7.5% or more by weight, still more preferably 8.5% or more by weight and particularly preferably 10% or more by weight, based on the whole amount of the composition or preparation of the present invention.
  • the upper limit of the amount used is not particularly limited, but is, for example, 30% by weight. If the preparation of the present invention is a preparation with a coating, such as a coated tablet, the amount used is the amount based on the whole amount of the component coated by the coating (whole amount of the component filled in the capsule, or whole amount of the component coated by the coating).
  • binder examples include polyvinylpyrrolidone, macrogol, and the same compounds as the excipients above. Specific examples of the binders include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, povidone (polyvinylpyrrolidone), and gum arabic powder.
  • the amount of binder used is preferably 0.1 to 50 parts by weight, and still more preferably 0.5 to 40 parts by weight, based on 100 parts by weight of the preparation.
  • Suitable examples of “lubricants” include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, and sodium stearyl fumarate.
  • surfactants or emulsifiers examples include polysorbate 80, polyoxyl 40 stearate, and lauromacrogol.
  • the colorant may be any colorant as long as it is permitted to be added to medicaments, and examples thereof include food dyes such as food yellow No. 5 (Sunset Yellow, U.S. food yellow No. 6), food red No. 2, and food blue No. 2, lake food colors, and iron sesquioxide.
  • food dyes such as food yellow No. 5 (Sunset Yellow, U.S. food yellow No. 6), food red No. 2, and food blue No. 2, lake food colors, and iron sesquioxide.
  • stabilizers include p-hydroxybenzoates such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.
  • the “diluent” is an inactive ingredient added to dilute or the like the active ingredient contained in the preparation.
  • excipients such as lactose or starch, sucrose and the like are used as the inactive ingredient in solid preparations such as granules.
  • the “fluidizer” is used to improve the fluidity of mixed powders and granules, and typical examples thereof include talc, and light anhydrous silicic acid and hydrated silicon dioxide, which are silicon dioxides.
  • light anhydrous silicic acid may be any compound composed mainly of hydrated silicon dioxide (SiO2 ⁇ nH2O) (n indicates an integer), and specific examples thereof include SYLYSIA 320 (trade name, Fuji Silysia Chemical Ltd.) and AEROSIL 200 (trade name, NIPPON AEROSIL Co., Ltd.).
  • Suitable examples of “preservatives” include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.
  • antioxidants include sulfites and ascorbic acid.
  • Two or more of the above additives may be used by mixing them in appropriate proportions.
  • Ethanol, phenol, chlorocresol, purified water, distilled water, and the like can be used as a solvent for producing a liquid.
  • granules means a granular material of nearly uniform shape and size obtained by granulating raw materials in powder, lump, solution, or molten liquid form by wet granulation, dry granulation, heated granulation or the like.
  • the average particle size of the granules is, for example, 150 ⁇ m or more, preferably 180 ⁇ m or more, more preferably 200 ⁇ m or more, still more preferably 250 ⁇ m or more, and particularly preferably 300 ⁇ m or more.
  • the upper limit of the average particle size of the granules is not particularly limited, but is, for example, 1 mm.
  • the average particle size is obtained by performing the following steps: (i) adding the sampled granulated products on top of a series of sieves with different pore sizes (pore sizes: 850, 500, 355, 250, 180, 106, 75, 53 and 0 ⁇ m), (ii) shaking the sieves for 3 minutes, (iii) measuring the weight of the granulated products remaining on each of the sieves, and (iv) calculating the particle size corresponding to a cumulative percentage of 50% from the pore size and cumulative percentage under the sieve of each sieve using the log-normal distribution approximation.
  • the particle size corresponding to a cumulative percentage of 50% is calculated from the pore size and cumulative percentage on the sieve of each sieve using Rosin-Rammler distribution.
  • the pharmaceutical composition used in the present invention may contain a surfactant.
  • surfactants preferably include monoalkyl sulfates such as sodium lauryl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, and sodium octadecyl sulfate, dioctyl sodium sulfosuccinate, sodium lauroyl sarcosinate, and sodium dodecylbenzenesulfonate.
  • ALK abnormality is a state presenting with an ALK gene abnormality or the expression of an ALK protein that is abnormal
  • ALK gene abnormality refers to a state in which activation of ALK is expected due to abnormalities found in the ALK gene, specifically, an ALK fusion gene, an activating gene mutation, or a copy number gain.
  • An “ALK protein that is abnormal” means an ALK protein that is not considered a normal ALK protein, and preferably means a protein expressed by a gene with an ALK gene abnormality. The presence of any ALK abnormality is also referred to as ALK-positive.
  • ALK a receptor-type tyrosine kinase
  • ALK fusion gene chromosomal inversion or translocation of a gene encoding a protein having the capability to multimerize with the ALK gene leads to the formation of a fusion gene of the two, which results in the expression of an ALK fusion protein that is a fusion of the two.
  • the ALK fusion protein permanently activates the ALK tyrosine kinase, which results in a continuous aberrant activation of the cell proliferation signals, and thereby causes the canceration of cells.
  • EML4, NPM, TPM3, TFG, ATIC, CLTC1, MSN, TPM4, ALO17, MYH9, RANBP2, CARS, SEC31L1, and the like are known as partner genes that form ALK fusion genes (“Guidance for ALK Gene Testing,” Biomarker Committee, the Japan Lung Cancer Society).
  • ALK fusion genes can be detected by fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), RT-PCR (including genome sequencing), and gene panel testing (hybrid-capture method and amplicon method), and includes known ALK fusion genes as well as unknown ALK fusion genes detected by these methods.
  • FISH fluorescence in situ hybridization
  • IHC immunohistochemistry
  • RT-PCR including genome sequencing
  • gene panel testing hybrid-capture method and amplicon method
  • the Vysis LSI ALK Break Apart Rearrangement Probe Kit (registered trademark), Vysis ALK Break Apart FISH Probe Kit (registered trademark) (Abbott), Histofine ALK iAEP (registered trademark) kit (Nichirei), Ventana OptiView ALK (D5F3) (Roche Diagnostics K.K.), FoundationOne (registered trademark) CDx Cancer Genomic Profile (Chugai Pharmaceutical Co., Ltd.), OncoGuide AmoyDx (registered trademark) ROS1 Fusion Gene Detection kit (RIKEN GENESIS Co., Ltd.), and Oncomine Dx Target Test Multi-CDx System (Life Technologies Japan Ltd.) can be used. If an ALK fusion gene or ALK fusion protein is detected by these kits, it is referred to as ALK fusion gene-positive.
  • An ALK activating gene mutation means that the ALK gene has been mutated to an active form by point or frameshift mutations.
  • G1128A, F1174L, F1174I, F1174S, R1192Q, F1245C, F1245L, Y1278S, M1166R, I1171N, R1275Q, and the like are known, but those newly detected using WGS or targeted capture sequencing are also included.
  • G1128A, F1174L, F1174I, F1174S, R1192Q, F1245C, F1245L, Y1278S, M1166R, R1275Q are preferred.
  • WGS whole genome sequencing
  • SNV single-nucleotide variants
  • INDEL insertions or deletions
  • CNV copy-number variations
  • SV large scale structural variations
  • exogenous genomes such as EBV and HTLV-1 genomes
  • Targeted capture sequencing is a method for detecting genetic abnormalities commonly used in “cancer gene panel testing”.
  • copy number gain refers to the presence of 2.5 or more copies (or a Log 2 ratio ⁇ 0.32) of a particular gene in a target diploid genome. If the copy number is 2.5, 50% of the cells used to define the copy number contain two copies of the gene as usual in diploid organisms and 50% of the cells used to define the copy number contain the usual two copies and one more copy of the gene (three copies of the gene in total). The copy number gain can be analyzed using MLPA and CGH.
  • MLPA Multiplex Ligation-dependent Probe Amplification
  • CGH (comparative genomic hybridization)/array CGH/SNPs array are methods for comprehensively analyzing genomic copy number variations. Genomic DNA extracted from tumor tissues and control tissues is labeled with different fluorescent dyes and then mixed and hybridized to metaphase chromosomes. The genomic copy number variation in tumor tissue is detected by observing the ratio of fluorescent signals.
  • Childhood cancer generally means a cancer occurring in children aged 15 years or less. Childhood cancers have different properties from adult cancers, with about half classified as hematologic tumors such as leukemia and lymphoma, 15% as brain tumors, and most pediatric solid tumors other than brain tumors as sarcomas, which occur deep in the body, or embryonal tumors, which originate from undifferentiated cells before their functions are yet determined in their respective body locations (https://www.ncc.go.jp/jp/rcc/about/paediatric_malignancies/index.html). Many ALK abnormalities due to ALK gene abnormalities or amplification/high expression of ALK are found in childhood cancers.
  • childhood cancers in the present invention include pediatric malignant solid tumors and malignant lymphomas.
  • Examples of pediatric malignant solid tumors include inflammatory myofibroblastic tumor, rhabdomyosarcoma, Ewing sarcoma family of tumors (Ewing sarcoma of the bone and other tissues, primitive neuroectodermal tumor (PNET), Askin's tumor (PNET occurring primarily in the chest wall), etc.), sarcomas such as leiomyosarcoma, central nervous system tumors such as neuroblastoma, glioma, neuroblastoma, and malignant peripheral nerve sheath tumor, cutaneous tumors such as malignant melanomas and Spitz tumors, retinoblastoma, lung cancers such as non-small cell lung cancer, renal cell carcinoma, anaplastic thyroid carcinoma, thymic carcinoma, and ovarian cancer, as well as epithelial tumor of the gallbladder and extrahepatic bile ducts, thyroid cancer, germ cell tumor, and malignant fibrous histiocytoma.
  • sarcomas such
  • Malignant melanomas include: (1) acral lentiginous melanoma (ALM), (2) superficial spreading melanoma (SSM), (3) nodular melanoma (NM), and (4) lentigo maligna melanoma (LMM).
  • ALM acral lentiginous melanoma
  • SSM superficial spreading melanoma
  • NM nodular melanoma
  • LMM lentigo maligna melanoma
  • Spitz tumors include malignant Spitz tumors, juvenile malignant melanoma, Spitzoid melanoma, and Spitz nevus-like melanoma.
  • malignant solid tumors are known to be rare cancers, with rare cancer being a generic term for malignant tumors (cancers) that occur less frequently. In Japan, the annual incidence is less than 6 cancer cases per 100,000 persons.
  • rare histological subtypes of non-rare cancers are also included.
  • rare histological subtypes of non-rare cancers are rare histological subtypes of esophagus cancer, stomach cancer, bowel cancer, breast cancer, liver cancer, and the like, and are specifically the cancer types classified in Table 1 below.
  • the rare histological subtypes of cancer that are not classified in Table 1 below and are reported to have an annual incidence of less than 6 cases per 100,000 persons for example, fibrolamellar carcinoma, a particular form of hepatocellular carcinoma
  • Malignant lymphoma is a rare childhood cancer and is classified into Hodgkin's lymphoma and non-Hodgkin's lymphoma. Childhood non-Hodgkin's lymphoma is further classified into mature b-cell lymphoma (Burkitt's lymphoma and diffuse large B-cell lymphoma), lymphoblastic lymphoma, and anaplastic large cell lymphoma, and is preferably anaplastic large cell lymphoma or diffuse large B-cell lymphoma.
  • Examples of the childhood cancer in the present invention preferably include inflammatory myofibroblastic tumor, neuroblastoma, thymic carcinoma, ovarian cancer, anaplastic thyroid carcinoma, neuroblastoma, Spitz tumor, malignant melanoma, rhabdomyosarcoma, Ewing's sarcoma, retinoblastoma, and glioma of the central nervous system.
  • inflammatory myofibroblastic tumor In another aspect of the present invention, inflammatory myofibroblastic tumor, diffuse large B-cell lymphoma, and neuroblastoma are preferred as the childhood cancer.
  • Yet another aspect of the present invention is a pharmaceutical composition for the treatment of childhood cancers such as thymic carcinoma, ovarian cancer, Spitz tumor, malignant melanoma, retinoblastoma, diffuse large B-cell lymphoma, or rare histological subtypes of stomach cancer, bowel cancer, breast cancer, or liver cancer, which have an ALK abnormality.
  • childhood cancers such as thymic carcinoma, ovarian cancer, Spitz tumor, malignant melanoma, retinoblastoma, diffuse large B-cell lymphoma, or rare histological subtypes of stomach cancer, bowel cancer, breast cancer, or liver cancer, which have an ALK abnormality.
  • recurrent means that the optimal response to the most recent treatment was a complete or partial remission
  • refractory means that the best response to the most recent treatment was stable or advanced.
  • Pathological conditions such as metastatic, curatively unresectable are also included.
  • Prior treatment failure means a case in which the prior treatment was ineffective and discontinued.
  • prior treatments include chemotherapy with other agents having similar or different mechanisms of action, radiation therapy, and surgery.
  • Specific examples include cases in which resistance is developed by the administration of crizotinib.
  • crizotinib an ALK inhibitor
  • Case reports of crizotinib on IMT with an ALK fusion gene (The New England journal of medicine. 2010 Oct. 28; 363(18): 1727-33), a US COG phase I trial in children with solid tumors or ALCL (The Lancet Oncology. 2013 May; 14(6): 472-80), and a phase II trial evaluating the efficacy of crizotinib in ALK fusion gene-positive ALCL and neuroblastoma, and other malignant solid tumors including ALK fusion gene positive IMT (Journal of clinical oncology 2017 Oct. 1; 35(28): 3215-21) have shown that crizotinib has clinical efficacy in these childhood cancers.
  • treatment means an act of administering the pharmaceutical composition of the present invention to a subject for the purpose of causing either the death of the cancer cells of a childhood cancer or a decrease in the number of those cells, suppressing the growth of cancer cells, and improving the various symptoms caused by the cancer.
  • the disease control rate is defined as the percentage of patients whose best overall response is either CR, PR, or SD, based on an overall evaluation determined by the combination of response of target lesions, response of non-target lesions, and appearance of new lesions, as will be described in Example 2.
  • It also includes slowing the progression of a childhood cancer compared to pre-treatment, the no-treatment group or the conventional treatment group, and improving general condition and clinical parameters compared to pre-treatment.
  • the size of the tumor is measured by imaging tests using CT (computed tomography) and MRI (magnetic resonance imaging). Tumor size is determined by the sum of tumor diameters. As the tumor diameter, the longest is measured for non-nodal lesions and the shortest for nodal lesions. Tumor diameter is measured by CT or MRI cross-sectional imaging.
  • PFS progression-free survival
  • RECIST Response Evaluation Criteria in Solid Tumors
  • CA-125 levels as a determinant of progression.
  • the pharmaceutical composition of the present invention comprises alectinib or a salt thereof in an amount of 20 mg to 160 mg in terms of free form as a daily dose, according to age in month, for childhood cancer patients aged 7 months or more and less than 24 months.
  • the above dose is equivalent to a daily dose of 2 mg to 16 mg in terms of a free form of alectinib or a salt thereof per kg of the male and female average body weight by age in month based on the “Technical report for Japanese National Growth Survey for infants and children in 2010” by the Ministry of Health, Labour and Welfare, for childhood cancer patients aged 7 months or more and less than 24 months.
  • alectinib or a salt thereof may be administered at a daily dose of 20 mg to 120 mg in terms of free form. More preferably, it may be administered at a daily dose of 20 mg, 40 mg, 80 mg, or 120 mg. Alternatively, a single dose of 20 mg may be administered once or twice daily, a single dose of 40 mg twice daily, or a single dose of 60 mg twice daily.
  • alectinib or a salt thereof in terms of free form may be administered at a daily dose of 40 mg to 120 mg in terms of free form. More preferably, it may be administered at a daily dose of 40 mg, 80 mg, or 120 mg. Alternatively, a single dose of 20 mg may be administered twice daily, a single dose of 40 mg twice daily, or a single dose of 60 mg twice daily.
  • alectinib or a salt thereof in terms of free form may be administered at a daily dose of 80 mg to 160 mg in terms of free form. More preferably, it may be administered at daily doses of 80 mg, 120 mg, or 160 mg. Alternatively, a single dose of 40 mg may be administered twice daily, a single dose of 60 mg twice daily, or a single dose of 80 mg twice daily.
  • Alectinib is known to be metabolized by the metabolic enzyme CYP3A4, but the existence of other metabolic pathways has also been suggested.
  • the activity and expression levels of metabolic enzymes differ between children and adults, and it is not clear how they change according to developmental stage in children. Therefore, the dosage and administration for children was established based on PBPK simulation assuming that a developmental process similar to that of CYP3A4 exists in the developmental profile of an unspecified metabolic enzyme in children, the lower limit was established at a dosage and administration that lowers the risk of the estimated child exposure exceeding adult exposure as much as possible, and the upper limit was established based on PBPK simulation assuming the same metabolic activity as adults from 0 month of age.
  • the dosage and administration is as described in the following (A) to (P).
  • a pharmaceutical composition for the treatment of childhood cancer with an ALK abnormality comprising:
  • a pharmaceutical composition for the treatment of childhood cancer with an ALK abnormality comprising:
  • a pharmaceutical composition for the treatment of childhood cancer with an ALK abnormality comprising:
  • a pharmaceutical composition for the treatment of childhood cancer with an ALK abnormality comprising:
  • a pharmaceutical composition for the treatment of childhood cancer with an ALK abnormality comprising:
  • a pharmaceutical composition for the treatment of childhood cancer with an ALK abnormality comprising:
  • a pharmaceutical composition for the treatment of childhood cancer with an ALK abnormality comprising:
  • a pharmaceutical composition for the treatment of childhood cancer with an ALK abnormality comprising:
  • a pharmaceutical composition for the treatment of childhood cancer with an ALK abnormality comprising:
  • a pharmaceutical composition for the treatment of childhood cancer with an ALK abnormality comprising:
  • a pharmaceutical composition for the treatment of childhood cancer with an ALK abnormality comprising:
  • a pharmaceutical composition for the treatment of childhood cancer with an ALK abnormality comprising:
  • a pharmaceutical composition for the treatment of childhood cancer with an ALK abnormality comprising:
  • a pharmaceutical composition for the treatment of childhood cancer with an ALK abnormality comprising:
  • a pharmaceutical composition for the treatment of childhood cancer with an ALK abnormality comprising:
  • a pharmaceutical composition for the treatment of childhood cancer with an ALK abnormality comprising:
  • the pharmaceutical composition of the present invention can be administered orally or by tube.
  • the pharmaceutical composition of the present invention can also be administered as a liquid or suspension by dissolving or disintegrating it in a liquid, such as water or a beverage, at the time of use.
  • a capsule may be administered orally using an oral jelly.
  • a capsule may be administered orally after disintegrating it with water or the like to form a suspension.
  • Tube administration is a method for administering a liquid using a tube inserted through the nose or mouth to the stomach (nasogastric tube or orogastric tube).
  • the capsule may be made into a suspension using warm water, water, or the like, and the suspension may be administered by tube.
  • the pharmaceutical composition of the present invention may be taken before, between, or after meals.
  • the pharmaceutical composition of the present invention may be used in combination with the following drugs and therapeutic interventions such as supportive care (including transfusion therapy) and symptomatic treatment, if deemed clinically necessary.
  • the maximum dosage and administration at which the average exposure at steady state is not exceeded when repeatedly administering 300 mg of the present drug twice daily (BID) to adults in the J-ALEX study (Japanese Phase III clinical trial, JO28928) was examined as a dosage and administration of alectinib for children.
  • the physiologically-based pharmacokinetic (PBPK) model was used to predict the exposure when alectinib is orally administered to the children.
  • Alectinib is primarily metabolized by CYP3A4.
  • CYP3A4 CYP3A4.
  • PBPK Physiologically Based Pharmacokinetic
  • PBPK model incorporating changes in age-dependent physiological parameters, including changes in body size associated with age and developmental changes in CYP3A4 expression, was constructed to predict the pediatric PK of alectinib.
  • the PBPK model was constructed by combining alectinib-specific physicochemical information (molecular weight, logP, pKa, etc.), and the in vitro and in vivo study results obtained so far, with the physiological information on the target population in the SimCYP (registered trademark) software (Certara, Sheffield, UK) (Table 2).
  • SimCYP registered trademark
  • A) Used for pediatric PBPK simulations. Absorption parameters was estimated by fitting clinical PK profiles observed in Japanese adult patients (JP28927: multiple p.o. administration with a standard meal, where formulation of alectinib was a 150 mg capsule). B) Adjusted by Kp scalar 0.26. C) V ss (475 L) after intravenous administration of alectinib was reported by Morcos et al*. To calculate a body-weight normalized value, 74.8 kg was used. This value was reported as the average value of the target subjects*. D) CYP2J2 was arbitrarily assigned although the true enzyme responsible is not known.
  • BID doses were estimated not to exceed the adult exposure: 20 mg, BID for children aged less than 3 months; 40 mg, BID for children aged 3 months or more and less than 7 months; 60 mg, BID for children aged 7 months or more and less than 20 months; and 80 mg, BID for children aged 20 months or more and less than 24 months ( FIG. 1 ). That is, the dosages and administrations listed in Table 4 are the maximum dosages and administrations for children under 24 months of age.
  • the physiological information on Japanese adults was replaced with that on Japanese children.
  • This physiological information on Japanese children is contained in the SimCYP (registered trademark) Pediatric module and includes parameters to take account of the age-dependent physiological and anatomical features of neonates (full term birth), infants and children (e.g. age-associated changes in organ size and blood flow, developmental changes in the expression of metabolic enzymes, renal function, and blood protein concentration, etc.). Then, for the PK prediction in children under the age of 2 years, the developmental changes in the enzyme expression involved in the elimination of alectinib were assumed.
  • CYP3A4 the major metabolic enzyme of alectinib, is considered to contribute to about 40% of hepatic metabolic clearance; however, the metabolic enzymes responsible for the remaining 60% of clearance have not yet been identified.
  • the pediatric developmental profile of unidentified metabolic enzymes was assumed to have a developmental process similar to that of CYP3A4, to lower the risk of the estimated child exposure exceeding adult exposure as much as possible.
  • the inter-individual variability in blood concentration on this simulation was calculated based on Japanese demographic data (Japanese pediatric demographic data source from Japanese Ministry of Health, Labour, and Welfare. Available from:
  • the pediatric dosage and administration was examined as the maximum dosage and administration at which the estimated exposure in children does not exceed the average exposure at steady state when repeatedly administering 300 mg of the present drug BID to adults in the J-ALEX study (Japanese Phase III clinical trial, JO28928, Lancet Volume 390, Issue 10089, 1-7 Jul. 2017, Pages 29-39).
  • the preparation used in the study is in capsule form, but the capsule is in principle administered by tube as a solution suspended in water since it is assumed to be difficult for children under the age of 2 years to swallow it.
  • C trough (trough value), which were observed in the J-ALEX study, was used as the index of exposure at BID administration.
  • C max maximum blood concentration
  • AUC ss area under the steady-state blood concentration-time curve
  • At least this dosage and administration can ensure efficacy and safety in cancers of children aged 7 months or more and less than 2 years with an ALK abnormality.
  • capsules of alectinib 20 mg capsules of alectinib are used in the present trial. Since the pediatric patients in the present trial often have difficulty taking capsules, oral jelly may be used, or a simple suspension method, in which the capsules are suspended in warm water to make a solution, can be used to administer orally or by tube.
  • Pediatric patients aged 7 months or more and less than 2 years are administered alectinib using the starting dosage until three courses are completed, even if their age changes or they pass the age of 2. From the fourth course until the patient turns 2 years old, administration is continued by changing the dosage according to Table 7, “Dose of alectinib per month of age in pediatric patients under the age of 2” according to the age in month at the start of each course. Once over 2 years old, the dose of alectinib is determined using the “Dose of alectinib per body weight in pediatric patients aged 2 years or more and 15 years or less” at the start of the next course. From then on, administration of alectinib is continued without dosage modification, even if there is weight fluctuation during the period of the trial.
  • Administration is preferably spaced at 8 hour intervals.
  • One course consists of 28 days, and treatment is continued unless the criteria for discontinuation of protocol treatment are met.
  • oral administration will be continued unless the criteria for course interruption are met, regardless of the time of evaluation within each course.
  • a special cohort of 1-6 young pediatric patients who are unable to take capsules orally (“simple suspension cohort”) is established and administered alectinib by a simple suspension. Details of the suspension method and oral administration method are described in the “Procedures for simple suspension cohort”. A single dose of alectinib is administered according to Table 7.
  • a single dose is administered as a course 0 only for the first dose for pharmacokinetic evaluation after a single dose.
  • the investigational drug is taken once in the morning on day 1 (C0day1) only.
  • the evening dose is not taken, and then administration is stopped for 2 days.
  • administration of alectinib is started from course 1, without single dose administration (course 0).
  • Imaging tests for tumor assessment are performed every 8 weeks until 24 weeks and every 12 weeks after 25 weeks, without change once the treatment protocol has started, even if there was a delay in starting the course.
  • the same modality and imaging conditions used in the pre-enrollment assessment are used*. Imaging tests are allowed within ⁇ 7 days of the above stipulated date.
  • Measurement of the blood concentration of alectinib is performed in the special cohort, or in patients having a body weight of less than 15 kg and from whom PK blood samples for pharmacokinetic evaluation can be collected.
  • the volume of a single blood collection for measuring the blood concentration of alectinib is 2 mL, and the points of blood collection are shown in the table below (however, for a body weight of less than 10 kg, the volume of a single blood collection is 1.5 mL).
  • “administration” in Table 9 refers to the first oral administration of the day.
  • the volume of a single blood collection should be 1.5 mL for patients having a body weight of less than 10 kg.
  • the total volume of blood collection for course 0 should be 10.5 mL for a body weight of less than 10 kg.
  • the total volume of blood collection for course 1 should be 12 mL for a body weight of less than 10 kg. [Notes] Referring to the standard for blood collection in sick children (21), the volume of blood collection should not exceed 3 mL/kg per day and 10% of total body blood volume (8 mL/kg) at 8 weeks.
  • the tumor shrinkage response was evaluated according to the following procedure in accordance with the “New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1), Japanese translation version by JCOG.”
  • neoplastic lesions prior to enrollment are identified by contrast-enhanced CT of the head, chest, abdomen, and pelvis (slice thickness: 5 mm or less), and each lesion is classified as a “measurable lesion” or “non-measurable lesion”.
  • measurable lesions found at enrollment up to 5 in order of increasing diameter (longest diameter for non-nodal lesions and shortest diameter for nodal lesions) and up to 2 per organ* are selected as target lesions.
  • All lesions not selected as target lesions, whether measurable or not, are recorded as non-target lesions. Multiple non-target lesions in the same organ are recorded as one lesion (e.g., multiple enlarged pelvic lymph nodes, multiple liver metastases).
  • Target and non-target lesions are evaluated at 8, 16, and 24 weeks, and every 12 weeks thereafter according to “4. Evaluation of efficacy” using the same testing method as at enrollment, regardless of any delay in starting the course, and the diameter of the target lesions and disappearance or progression of non-target lesions is recorded.
  • the rate of reduction or increase in the sum of diameters is calculated as follows.
  • non-target lesions persists (including the persistence of nodal non-target lesions with a shortest diameter of 10 mm or more)
  • Overall response is determined from the combination of response of target lesions, response of non-target lesions, and appearance of new lesions according to Table 10 at 8, 16, and 24 weeks, and every 12 weeks thereafter. In the absence of non-target lesions at baseline, the overall response is determined by the response of target lesions and the appearance of new lesions.
  • the overall response is considered as “good” in the order of CR>PR>SD>PD>NE, and the Best Overall Response is determined according to the following criteria. If the definition of several categories is met, it should be classified into the better one in the order of CR>PR>SD>PD>NE.
  • CR is obtained as overall response for two or more times in a row at intervals of 4 weeks (28 days) or more.
  • the pharmaceutical composition of the present invention is particularly useful as a therapeutic drug for cancer in children aged less than 24 months.

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